The Luddites Are Always At The Gate

Prevalence of Multimorbidity with Age (left) and Sex (Right) from Reference 2 per Creative Commons Attribution License.

I noticed a Twitter feed about a blog piece on the complexity of multiple illnesses and the need for primary care (1).  If the post would have stopped there it would be impossible to disagree with.  Unfortunately in the usual manner of the blogosphere - for every group elevated another needs to pay the price.  In this case, the natural target would be the specialists.

The basic argument is that as people get older they end up with more chronic diseases. That should not be surprising to anyone - see the graphic above and click on it to enlarge.  People who accumulate more of these chronic illnesses are the most expensive people to care for in the health care system.  Also no surprise, but somewhat of an overstatement.  In the USA, it is quite easy to be sailing along disease free and suddenly develop an illness that places you in the top tier of treatment costs.  Cancer is a clear example.  One of my colleagues told me that the total cost of treatment for breast cancer in one of his relatives was over $1 million dollars.  That explains the main motivation for health insurance in the USA, any serious illness can lead to bankruptcy without insurance.

The argument continues that the predominate model of care is that physicians diagnose, treat, and cure illness in episodes of care rather than maintaining people with chronic illnesses.  The author concludes that physician specializing in organs or parts of organs are not equipped to deal with the problem.  He refers to remorseless specialization and subspecialization as being the problem.  He concludes that doctors and patients seem to be going in opposite directions because of this.

That is not what I am seeing.  In the USA, one of the main metrics followed in surgical specialties these days is the volume and outcomes of surgeries.  Several references point out that surgical volumes and good outcomes are directly correlated.  For that reason I found a neurosurgeon who was doing two transphenoidal pituitary adenoma resections per day for years rather than one who had done a total of 9 lifetime when my wife needed resection of a growth hormone secreting adenoma from her pituitary gland.  It has been 9 years since the resection and no recurrence of the tumor or endocrine markers.  She has not seen the surgeon again in that time but is followed by a primary care physician and an endocrinologist.
      
The beauty of the American health system if there is any is that you can see a broad array of specialists in any moderate population center.  The author was astonished to find that the British Journal of Ophthalmology has a different editor for every layer of the eye.  I think that it is equally astonishing that in most American cities you can wake up with symptoms of a retinal detachment and be seen by an eye specialist within hours. If it looks like you have a true acute retinal detachment - you will be referred to a retinal or vitreous specialist and have definitive treatment the same day or the next.  The laser surgical technique is far superior to what was being done 20 years ago and can be accomplished in an office in as little as 20 minutes.  That surgery prevents blindness and the need for riskier surgery.  Within a few decades, ophthalmology has evolved to a very effective and efficient specialty that covers a broad range of eye diseases with relatively few physicians.  The advantage of specialists in this case is clear cut and directly addresses patients needs.  In fact, the problems that ophthalmologists treat are barely addressed in medical schools.  The problem is not that the specialists don't know primary care.  The problem is that it is impossible for primary care physicians to recognize and diagnose eye conditions and treat them.

With regard to the knowledge in each specialty, a late friend of mine who happened to be an ophthalmologist put it this way: "Each specialty expands to cover roughly equal amounts of information."  At the time of his statement - books were the standard and he pointed out that each specialty had 2 - 3 volume sets of several thousand pages.  I haven't seen an information age comparisons - but I think that the concept is a good approximation.

That is not to say that specialists are "better" than primary care physicians.  If anything. primary care physicians and specialists count on the fact that those primary care physicians can manage all of the patients health problems except for the one being addressed by the specialist.  Specialists count on primary care physicians for preoperative physical exams, referrals, and ongoing care after they have completed the consultation. The problem for some is that it sets up specialists and subspecialists as the superstars of medicine.  I am speculating about the problem because I certainly don't see it that way.  There is no doubt that some of these specialists are very highly compensated and I won't argue that is right or wrong.  Personal observation tells me that they work as hard as anyone and really don't have glamorous lifestyles.  Being on call to all of the emergency departments in an area for rare problems is not an easy job.  They are there to solve very specific problems, manage one particular illness, or advise the primary care physician about how they would do it and turn the care back over to them.   

Even with the inefficiencies of the American health care system - I think there is evidence of a reasonable distribution.  The neurosurgeon I referred to sees a catchment area of the entire Midwest.  Anyone with a pituitary tumor has access to his expertise.  The retinal specialists can be found generally in any area where there is a city of 50,000 people.  Since retinal tears/detachments, various retinopathies, and macular degeneration are widespread and in many cases age-related these clinics have a much broader representation and provide good access to large segments of the population.     

Over the years that I have been in practice there have been many primary care initiatives. The first initiative was actually threatening to put specialists out of business.  That turned out just to be a managed care organization (MCO) tactic.  The second wave was forcing MCO primary care physicians to authorize all approvals for specialty care - the so-called primary care gatekeeper approach.  I can't imagine how much time that wasted.  After managed care organizations realized that they could hire specialists and monopolize them - they also realized that they could make money by "managing" them.  That was not 100% effective because now specialists realized they finally had some leverage against managers and could take their business off campus and manage it more effectively themselves.  I have seen many variations of pro-primary care and anti-specialist rhetoric over the years.

The problem is that the money never follows the rhetoric.  Instead of just paying lip service to primary care why not actually pay them for managing multiple morbidities in an aging population? Why not recognize their expertise?  There is no health care company that I am aware of that comes close. MCOs are trying every way possible to reimburse primary care at rates so low - they barely cover the overhead.  Government payers are doing the exact same thing.  The government programs like Medicare are so bad that many primary care MDs are disenrolling and engaging in a cash only practice.

On the academic side, where are the primary care centers of excellence?  Where are the mission statements about managing multimorbidities and being the best possible specialists to do that?  Primary care specialists need to own and promote their expertise, especially how they interface with specialists.

It turns out that there is plenty of room for both primary and specialty care in modern high tech medicine.  Specialization should be remorseless and managing multimorbities is as specialized as laser surgery on a retina.  Once again it appears that the real problems of health care systems are being projected on physicians when they have developed critical treatments that were not around even 20 years ago.

The idea that we should travel back to that point in time - is totally unacceptable to me and the tens of millions of other patients who have benefited from these developments.

George Dawson, MD, DFAPA




References:     

1:  Richard Smith. Doctors and patients heading in opposite directions.  BMJ Opinion. BMJ Feb 1, 2018.  Link.

2: Violan C, Foguet-Boreu Q, Flores-Mateo G, Salisbury C, Blom J, Freitag M,Glynn L, Muth C, Valderas JM. Prevalence, determinants and patterns of multimorbidity in primary care: a systematic review of observational studies. PLoS One. 2014 Jul 21;9(7): e102149. doi: 10.1371/journal.pone.0102149. eCollection 2014. Review. PubMed PMID: 25048354; PubMed Central PMCID: PMC4105594.

The Most Important Decision In Your Life......

See Complete Reference Below

I thought a while about how to write this.   There are a lot of opinions out there about how a decision like this one should be philosophical or religious.  After practicing psychiatry for over 30 years I have to come down on the side of practical.  The most practical decision I think that anybody can make is to stop using intoxicants, at least to the point of intoxication.  I don't really care what your current intoxicant is.  It could be alcohol or cannabis or heroin.  Deciding to stop it will only improve your life and the lives of your family and friends for any number of reasons.  At this point I am a witness to the thousands of people who have stopped and seen those improvements.  I am also a witness to the unfortunate thousands of people who did not stop and ended up dead, incarcerated, homeless, chronically mentally ill, in nursing homes, or leading miserable lives.  I am not naive enough to think that my little argument here is going to make that much of a difference and will elaborate on that in the paragraphs that follow.

One counter issue that I want to address as early as possible because it is often used to short circuit arguments against intoxicants is what I consider an American pro-intoxicants argument.  It certainly can exist in other cultures, but I am restricting my comments to Americans because of the pervasive attitudes about intoxicants.  The most obvious attitude is alcohol and drug use as a rite of passage to adulthood.  This is a well documented phenomenon rationalized at several levels.  Common examples include: "If one is old enough to vote or go to war they are old enough to drink."  There is abundant current evidence that 18-21 year olds if anything are exposing brains that are neurodevelopmentally immature to the effects of alcohol and street drugs - often at toxic levels.  Rational arguments against exposure are not likely to have much of an impact on a population segment in the throes of the invulnerability of youth.  Even apart from the brain based argument, the driving and risk taking behavior of this group is well documented.  Adding intoxicants to the mix is not likely to alter those decisions in a positive way.

An extension of the rite of passage argument is the rights argument as in "Alcohol and tobacco are legal substances and therefore I have a right to use them."  There is no doubt that is true, but the right is limited.  Only people of a certain age can use these compounds and in the case of intoxicants that can affect public safety - their use is even more limited.  People who I have seen invoke the rights argument are generally not talking about limited rights.  The modern version of the rights argument is that "no one should have the right to tell me what I can put in my body.  On that basis all drugs should be legal and easily accessible".  A complementary argument is: "Alcohol and tobacco kill more people every year than (fill in favorite intoxicant here) and therefore I should be able to use it."  Another complementary argument that often gets more support is: "The War on Drugs is a complete failure.  All drugs should be legal and that way we can tax it and make a profit from it.  We can put the cartels out of business."  The rights argument frames an idyllic drug consuming society immune to the medical problems of acute intoxication and addiction as well as all of the associated social and legal problems.  Extreme arguments like this suggest to me that they are driven in part by desperation.  Of course intoxicants need to be regulated - we already have ample evidence of what happens when they are not.  The basic problem that they reinforce their own use at increasing levels cannot be ignored.  Tax on intoxicants is generally an unreliable revenue source when the total cost to the taxpayers for that intoxicant and the fact that revenue is diverted away from covering those costs.
  
A second cultural phenomenon is the use of intoxicants for celebrations.  Weddings, funerals, and various parties often result in the excessive consumption of alcohol. I attended a funeral where the clergyman addressed half of the audience and suggested that an AA meeting might be in order afterwards.  The deceased was probably a victim of excessive alcohol use.  Although alcohol remains predominant in many of these settings, since the 1970s second and third intoxicants are also common.  The relevant consideration is whether these celebrations can occur without the intoxicants.  Interestingly, that decision may come down to the cost of having an "open bar" versus less expensive alcohol on tap. 

A third consideration is the subculture of extreme use.  Many states are notorious for per capita alcohol consumption, binge drinking, and driving after drinking too much.  I don't think that the problem has been well studied, but growing up in a heavy drinking or using culture exposes anyone to early use and reinforcement that are both precursors to problematic use. 

There are several arguments in the popular media that seek to minimize the potential impact of drugs on your life.  Think about the counterarguments:



1.  If I don't have a diagnosis of alcoholism or drug addiction my pattern of using intoxicants is not a problem:

The most absurd presentation of this argument was the idea that a significant number of binge drinkers do not meet diagnostic criteria for alcohol use disorder.  I can't count the number of people who I know that have had their lives ruined or ended by a single drinking binge.  Many high schools in the US started a senior party strategy because so many students were killed around the time of graduation parties due to acute alcohol intoxication.  The drivers in these cases were not alcoholics.  They were high school seniors many of whom had limited exposure to alcohol before the fatal accident.  Binge drinking and acute intoxication is associated with a long line of accidental deaths, alcohol poisoning deaths, suicides, homicides, intimate partner violence, rapes, and other crimes.  All preventable by not binge drinking or more importantly getting intoxicated in the first place.  The same pattern follows every other intoxicant.  If you put yourself in a mentally compromised state in practically any setting - bad things will happen whether you have been diagnosed with a substance use disorder or not.

2.  Alcohol is a heart healthy beverage:

The CDC and the American Heart Association both recommend moderate intakes of alcohol and they define that as one standard drink of alcohol per day for women and one or two standard drinks for men.  This is based on data that shows that these amounts of alcohol may confer reduced risk for heart disease but that higher amounts increase risk.

3.  Intoxicants can be good for your health - some are natural medicines:

The great natural argument leaves a lot to be desired. It's like listening to that guy in a bar tell you that his doctor told him he could drink as much wine as he wanted because it was a natural beverage and then realizing that he is standing in a puddle of his own urine. Peak alcohol consumption in the US occurred at time when it was considered a medication in the early part of the 19th century.  The current best example is cannabis, a substance that has been around for at least 10 centuries and suddenly it is a miracle cure for everything.  The obvious question is why that wasn't noticed in that last 1,000 years. 

4.  Alcohol and drug use disorders are not diseases - it is a question of choice and therefore I have nothing to worry about:

Despite what you may read on some online blog, in opinion polls most people consider alcoholism and addictions to be diseases.  Almost everyone has had some contact with people who have these problems and they see that the usual negative consequences that cause most people to correct their behavior - have no effect on the addicted.  There is no or at least limited capacity for self correction.

5.  I am a libertarian and I believe that all intoxicants and drugs should be legal - I should be the only person deciding what goes into my body:

A familiar argument that ignores human history. The reason that there are controls on addictive drugs is because a significant part of the population will use them in an uncontrolled manner and that generally leads to a chaotic society with all of the costs of that chaos. The more free access there is - the more addiction and chaos.

This argument implies that everyone is the best judge of "what I put in my body" based on political beliefs. There is no evidence that is true.

6.  I am an adult and if I want to have a drink - I will have a drink:

That is a minor variation of the libertarian argument for non-libertarians.  It is basically a truism - yes of course unless you are prohibited by law (and some people are) you can have a drink.  Doing something basically because you can strikes me as a shallow argument. Looking at what happened during Prohibition, I think it is safe to say that the right to drink was preserved by a relatively vocal minority of people who want to drink.  They want to drink for the previously cited cultural reasons and in fact there were some famous exceptions to Prohibition that were based on purported religious ceremony and requirements for alcohol. 

A similar argument is that if a person wants to feel high "there is nothing wrong with that."  At a superficial level and strictly speaking that is true as long as the level of intoxication doesn't lead to medical, safety, or interpersonal problems. The larger question is whether there is something better to do. Let's define better as another recreation that leaves you better off than using intoxicants.  In that case walking around the block is better than getting stoned.

7.  It is part of my creative process:  

There are reviews and books written about how creative people have used drugs and alcohol to enhance their creative process.  These works are by their nature anecdotal.  I am unaware of any controlled sober group and their creative process but it is likely that they exist in large numbers.

8. I am self -medicating and need it to treat insomnia, anxiety, depression, and/or pain:

Self medication implies that intoxicants are actual treatments for these problems. If you talk to any person who uses this strategy - the amount of relief lasts for a few hours.  People tell me: "Look doc - if you can't get rid of this anxiety - I know how to get rid of it for a few hours."  Using alcohol, street drugs, or diverted prescription medications is usually a recipe for worsening symptoms and tolerance.  In that setting people often have the idea that more drugs will bring back the few hours of relief and there are always examples of associated catastrophes in the news. 

9.  The political argument that by allowing universal access to drugs - the cartels will be out out of business - 

Very common to hear that all drugs should be legalized and hear this argument in the next breath.  Most of the people making this argument seem naive to fact that black markets still exist with legal intoxicants.  In the WHO Global status report on alcohol and health 2014, 24.8% of the alcohol consumed was outside of government control.  In the US, it was 0.5 liters of a total of 9.2 liters per capita.  For tobacco the black market is somewhere between 8.5 and 21% of sales. In Colorado there is currently mixed concern about the possibility that drug traffickers are in plain sight, continuing to grow cannabis in remote areas and transport to other states, but reliable information is not available. In the case of heroin, the current impetus for its use is that it is 25% the cost of diverted pharmaceutical opioids.  In the worst case scenario of legalized opioids with no control is it realistic to consider governments regulating heroin at that low cost to consumers?  If not it is a recipe for continued uncontrolled black markets. 

10.  The "You are an prohibitionist" counterargument:

Whenever I present any of my arguments for avoiding intoxicants in the list above, there is the inevitably that some very angry guy accuses me of being a prohibitionist.  I don't know how much weight that ad hominem carries but I always find it amusing. If prohibition worked, I would not need to make these arguments.  My blog is one of the few places where you can see a graphic of how things went during prohibition and it obviously wasn't good.
 
Believe me - you can go through life without ever taking a drink, smoking a joint, snorting cocaine, or injecting heroin and not miss it.  The best case scenario is that it adds nothing to your quality of life.  It is also tempting to think that you have plenty of time to quit later.  With that plan many people either never quit or realize when they are 40 years old that they have been in a fog for 20 years.  Addictions sneak up on you and steal what should be your most productive years.

In fact none of the people with addictions who I talk to ever started out believing that one day they would end up with an alcohol or drug use problem.  Recognizing all of the defective arguments listed above is a good first step.  The most important ability to prevent addictions is self correcting abstinence.  If you wake up one day and realize you dodged a bullet when you were intoxicated, think long and hard about avoiding that situation again.

If you can't - you may have a serious problem.


George Dawson, MD, DFAPA



Supplementary:

Graphic at the top is from:

Lavallee RA, Yi H.  Surveillance Report #92: Apparent per capita alcohol consumption: national, state, and regional trends, 1977-2009.  US Department of Health and Human Services. Public Health Service.  August 2011.  Link.

My Opinion on Community Mental Health From 1989....

A friend of mine who also worked with me as an RN on an acute care psychiatric unit sent me this newspaper clip from 1989.  It is from the St. Paul Pioneer Press.  At that time I had just started working on an acute care inpatient unit at St. Paul-Ramsey Medical Center (SPRMC) after working in a community mental health center (CMHC) for three years.  The CMHC was in northern Wisconsin and SPRMC is in St. Paul, Minnesota.  In this brief letter to the editor, I was listing the style points between both systems.  Wisconsin was known to be an innovator in community mental health essentially inventing active outreach, providing meaningful crisis intervention services, and active case management with a goal of keeping people with severe mental illnesses in their own apartments in the community and out of hospitals.  Anyone with any experience at all realizes that this is the best approach to the problem.  We did not worry about it at the time, but it also kept people out of jail.  We had working relationships with law enforcement and would often see people in jail and facilitate their treatment there and transition back to the community.

As the medical director of a CMHC in Wisconsin in those days, I had a team meeting with case managers and nursing staff every morning.  We discussed crises and treatment plans for the 100 to 110 individuals under our care.  After that meeting everyone (except me) was driving off to meet our patients in the community.  We had an exemplary record of helping these folks stay out of the hospital and our case managers would go to the hospital and help get them discharged if they were at baseline.  We knew the resources, landlords, relatives, doctors, and local crisis housing.  We worked within a system that had a single-minded focus of supporting people in the community and at the administrative level we had state support mandated that the "money follows the client".  That did involve an incredible amount of paper work on the part of our case managers and needing to deal with a county bureaucrat but there were clear significant advantages over other systems.

Flashing forward 30 years has there been much progress?  I can say with certainly there has been absolutely no progress on the Minnesota side.  They have funded some assertive community treatment (ACT) teams but there is still a rationing mentality.  I heard the rationing mentality recently restated by the current head of the state hospital system.  Minnesota currently has a large steady state population of chronically mentally ill patients circulating through emergency departments, available beds, jails, and homelessness.  There is limited bed availability to the point that outpatient psychiatrists have to send their patients to the emergency department (ED) rather than referring them directly to affiliated hospital because they know there are no beds. That is also true for patients who need electroconvulsive therapy.  The constant stream of people to the ED creates a backlog there and getting patients out occurs only if they are held long enough for an inpatient bed to open, discharged untreated, or transferred to another hospital often several counties away.  In the meantime, the state hospital system has been reduced.

In a November meeting of the Minnesota Psychiatric Society (MPS), Kylee Ann Stevens, MD the Executive Director Direct Care and Treatment of the state hospital system provided some numbers for mental illness treatment but not addiction resources.  Those numbers are summarized in the graphic below.      

It is apparent by inspection that there has been a massive reduction is state hospital beds.  Just over the course of my career they have dropped by over 1,000%.  The bed situation is compounded by a "48 hour rule" enacted in 2014 that states that all patients with a question of mental competency in jails or correctional institutes must be admitted to a state facility within 48 hours.  That gives county Sheriffs preferred access to state hospital beds over treating psychiatrists.  Rather than look at recommended hospital beds per population the state does not plan to try to increase the beds.  A quote from the  National Association of State Mental Health Program Directors (NASMHPD) that "Building more inpatient bed capacity to meet demand is unsustainable" provided the rationale.  The conflict of interest there is obvious.  State Directors are basically accountable to politicians and bureaucrats who want to ration state supported health care especially to those with the least vocal advocacy. At one point in Minnesota over 11,000 beds were sustainable. The only thing different today is politics.

There is also a chronic unanswered question that has been hanging in the air for the last 20 years.  Did Minnesota intend to just shut down the state hospital system entirely? Certainly the trajectory of bed closures was on track to do that.  In the MPS meeting we never learned what the absolute minimum number of beds was.  In talking with doctors and nurses who worked in that system they certainly thought that was the goal.  The current minimalist system may be in place by default rather than design - the end product of a failed attempt to close down all of the state hospital beds.

So Minnesota continues to flounder.  What about Wisconsin?  I don't think that their inpatient bed capacity is much better but I don't have the exact number.  The community mental health movement is still alive and well but I am aware of no significant innovation.  The Wisconsin Mental Health Statutes appear to have expanded significantly and law enforcement seems to have assumed more of a gatekeeper role in emergency treatment.  I can't comment on whether the Wisconsin system is more cost effective and patient centered than Minnesota but I invite clinicians to comment on that.

Relative to the initial news clip - progress in general in the treatment of psychiatric disorders is not a word that can be used.  Politicians run these systems and not physicians.  As long as that is true we can depend on no progress.

George Dawson, MD, DFAPA  

See also:

Minnesota's Abandonment Of Severely Mentally Ill - Nearly Complete

News Flash From the StarTribune - Psychiatric Patients Have "Nowhere To Go"

Minnesota's Mental Health Crisis - The Logical Conclusion of 30 years of Rationing

Running the numbers Minnesota has 3.2 state hospital beds for 100,000 people.

A Short (11 minute) Film About Alcoholism - Breakfast Wine

"In Ireland, they say it takes just 3 alcoholics to keep a small bar running in a country town....."



I ran into this film last week and was impressed enough to write this post about it.  It is an award winning short film about four people in a pub in rural Ireland and events that transpired on a certain day.  Given the availability and brevity of the film, I encourage anyone interested to view the video before reading this post.

You can go to any number of Saturday Night Live skits and see alcoholics ridiculed.  This film takes the problem more seriously. What you see will depend on your experience observing and interacting with people who have an alcohol problem.

To set the scene, the film begins with the quote posted at the top of this page.  We see two middle-aged men standing outside a pub waiting for it to open.  The owner shows up.  They all enter and the two men who were waiting commence drinking pints of Guinness.  Over the duration of the time lapse in the film they each drink 6 pints of Guinness - the first two in what seems fairly rapid succession.

After they put down about two pints a young woman enters, asks them about the availability of wine.  After getting their recommendations she proceeds to drink the first glass rapidly. Over the time lapsed in the film she drinks a total of 4-187.5 ml bottles. The pub owner and the two men in the bar seem impressed with her ability to drink, but they are also impressed with her ability as a ranconteur.  She tells a fable about getting rid of all motor transport and lining people up against the wall and shooting them.  She moves on to describe severe physical abuse by her husband and shows lacerations on her wrists where she was tied up on the garage floor.  She tells them what her husband was saying to her when he became abusive and does not miss a beat.  She sarcastically dismisses her rant by saying "I should have seen it coming."  At that point she says good bye and the pub owner tells her what the opening time for the pub is every day.  She thanks him for the information and walks out.  The men are clearly impressed with her and one of them longingly touches the stool where she was  sitting.

At the level of entertainment, I can see why this is an award winning short.  The writing and acting are good.  The woman in the scene, actress Ruth Bradley is a compelling screen presence.  She plays this  role perfectly. It is a plausible scene from any bar - Irish or American. From the standpoint of an addiction psychiatrist - what is wrong with this picture?

The alcohol consumed per unit time is a red flag.  The CDC defines binge drinking as probably occurring if a woman consumes 4 or more drinks or a man consumes 5 or more in 2 hours.  The time span of this film may be subject to debate but I counted 6 pints of Guinness per man or 9.6 standard drinks and 750 ml wine (4 - 187.5 ml bottles) or 5 standard drinks for the woman.  It is clear from the depiction by the actors that they are drinking these beverages at times like water.  In bars or pubs bad things tend to happen when the patrons are binge drinking. Binge drinking alone whether it is associated with a diagnosis of alcohol use problems has associated mortality and morbidity per the CDC site.

 There is a high tolerance for unusual behavior in the pub.  One of the men leaves and his behavior is discussed among the remaining people.  In another scene marking the sixth pint he becomes irate with his associate and that behavior is translated as an acknowledgement that he does want another pint.  The woman had two discrete rants about motor vehicles and the violence she has sustained by her husband and immediately resumes a normal even joking manner.  The men are intensely interested in this woman, she breaks up their routine, is attractive to them and is charismatic.  Their response to her description of the violence she has sustained and even the presentation of her wrist lacerations is definitely muted. No one is interested in the violence or her newly acquired wounds, everyone is interested in moving on as soon as possible.

The dynamic that jumps out at me whether I am listening to heavy drinkers talk about relationships or observing them first hand in bars is grandiosity.  Grandiosity can be a feature of mood disorders or narcissism.  One theory of grandiosity in narcissism is that there is an inadequate mental representation of affirming objects representing attributes or real relationships in the environment.  If people with those attributes are absent or the people present have an inadequate positive affiliation with the person in question they can form their own representations.  That leads to grandiosity and narcissism  as an amplification of a deficient process with more realistic balances.  In alcoholism this can occur as a reaction to the hopelessness of the addiction and its sequelae.  As an example, a bar full of middle-aged men with alcoholic liver disease betting on who is going to die first.  Sometimes it occurs on a larger scale - the family that supports their father's grandiose statements about drinking himself to death during a hospitalization for recurrent hepatic encephalopathy from alcoholic cirrhosis.  The person involved comes across as though they are indestructible - but at a deeper level they cannot reconcile the severity of their illness and their inability to stop drinking.

That is what I think the female character brings to this scene.  She is clearly in an abusive marriage that she fled earlier the same day that she comes into the pub.  She does not appear to be traumatized at all until she demonstrates the injuries and even then she is loudly mocking her husband and eventually herself: "I should have seen it coming!"  The men seem transfixed on this story - unable to challenge it or accept the reality of her status as an abused wife.

I saw one comment posted on the YouTube site from a person who watched this film on an airline flight.  He was left thinking about the lives of the people in the film and what happened to them.  That is natural enough and something I wondered when I encountered a heavily intoxicated young woman in Boston and tried to help her.  To me it is always a lesson in the dynamics of heavy alcohol use.  There is an element of intoxication involved, but there is more than that driving a lot of the interpersonal behaviors and what you see happening in a pub or bar.

Defensive behavior about the inability to stop can be part of that.                       

 

George Dawson, MD, DFAPA

Lithium for Depression.....

I bought a copy of Manic Depressive Illness when it first came out in 1990.  One of the more interesting aspects of the book was the commentary on the use of lithium monotherapy for unipolar depression.  That discussion is limited to about three pages and reviewed the work to date.  In the opening paragraph there is this astonishing line:  "Overall, the result of open studies suggest that lithium is as effective in preventing unipolar illness as it is in preventing bipolar illness."  At the time there were 4 controlled studies (3-6) looking at the issue of maintenance therapy in mixed unipolar and bipolar groups.  Three of the four studies showed no difference between groups.  The fourth study was inconlusive due to a high dropout rate.  Subsequent analyses by Schou and Baldessarini and Tohen concluded that the protective effects of lithium in preventing recurrent depressive episodes was good.  In Schou's reanalysis he showed that the relapse rate in one year on lithium for unipolar depression was 22% (compared with a 20% relapse rate for bipolar disorder) and the rates for antidepressants at one year were 35% for unipolar depression and 65% for bipolar disorder (relative to placebo of 67-68% relapse rate).

Since that early open research there has been only randomized controlled clinical trial (RCT) of lithium versus placebo antidepressant augmentation (7).  In that study 7/15 patients treated with placebo relapsed and one suicided.  In the lithium treated group 0/14 relapsed.  The authors recommended that patients who respond to lithium augmentation be maintained on it for at least 6 months.  Additional clinical parameters of interest in the treated group was an average lithium dose of 980 mg, an average Li level of 0.65 mmol/L, and a response time of 17.5 days in acute treatment.  This is interesting because many psychiatrists using lithium augmentation were taught to stop at 600 mg/day and accept the associated lower levels.

My point in the introductory paragraph here is that it has been known for some time that lithium may have a role in maintenance of unipolar depression in addition to bipolar depression - even though it is hardly ever used that way int he United States.  In the US, patients typically endure a long series of antidepressant trials or augmentation strategies if the initial trails are ineffective.  There is always the problems of whether the antidepressant has lost its effect or not and the associated difficulty of trying to determine what other factors may be operative.  Lithium has been used for the past three decades as an augmenting agent - added to antidepressants.  Typically a lower dose is used (600 mg/day) and that may offer a lower chance of toxicity and less need for monitoring blood levels.

Against this backdrop, a very interesting paper by Tiihonen, et al came out last year (2). For reasons that will follow, I consider this to be one of the most important papers for clinical psychiatrists from 2017.  The authors provide a sound rationale for their study, specifically the advantages of a large scale epidemiological/observational study over an RCT or the Cochrane meta-analysis of RCTs.  That meta-analysis (like most Cochrane meta-analyses) concluded that the number of subjects included was too small to come to a statistically significant conclusion.

The study was conducted in Finland.  The authors point out that each citizen has a unique identifier that facilitates the design of large inclusive observational studies across health care databases.  The sample in this case was a study cohort (N= 123,712) of patients who had been admitted to a hospital for unipolar depression between January 1, 1987 and December 31, 2012.  They had a comparison incident cohort (N=30004) that looked at new patients beginning on December 31, 1996 with no mental health diagnosis, hospital admissions for depression, exposure to the medications of interest, or history of outpatient care in the year prior to the start.  The purpose of the incident cohort was to look at the issue of survival bias. The primary outcome measure was risk of readmission in all patients admitted  for unipolar depression at least once between 1987 and 2012.  All cause admissions were a secondary outcome measure.  Medication use was estimated using the PRE2DUP mathematical modelling of the patient medication purchasing.  Each patient was used as their own control to eliminate selection bias.  I did not have access to the appendices from this study, so I will forgo further discussion of the statistical methodology without that data.

Mean hospitalizations for people who had used lithium was 4.3 (SD 6.9) for psychiatric admission and 7.8 (SD 9.1) for all cause admissions compared to 2.2(SD 3.1) and 5.8(SD 7.0) for those who had not indicating the lithium treated patient were more severely ill.  Using lithium significantly decreased the relapse risk.  Mean daily lithium dose was noted to be 765 mg.  Forest plots are contained in the body of the article looking at the hazard rations of readmission for several pharmacological treatments in both the study cohort and the incident cohort.  Forest plots looked at benzodiazepines, hypnotics, antipsychotics, and lithium +/- antidepressants.

Lithium monotherapy was superior to all other studied pharmacotherapies in preventing hospital readmissions.  Older antidepressants (amitriptyline and doxepin) and antipsychotics (clozapine sulpride, aripiprazole, and quetiapine) showed some efficacy in preventing hosptializations.  Benzodiazepines did not.  In the incident cohort where (survival bias was eliminated) the lithium effect on decreased rehospitalizations was more robust suggesting the effect size was more valid than for the total cohort.  They also did a secondary mortality assessment and showed that both lithium and antidepressants were associated with decreased overall mortality and no difference was observed for antipsychotics.

The authors recognize that there are significant adverse effects and limitations with the use of lithium.  They point out there are also possible advantages outside the treatment of mood disorders but there is a significant burden associated with taking it.  They recommend that is be considered for maintenance of a broader group of patients with unipolar depression.  In our antidepressant-centric society, I agree with their conclusion.  The effects in this study really cannot be ignored.  Lithium augmentation of antidepressants has been around for over 30 years.  It surfaced again the the STAR*D protocol.  I see patients who have been exclusively been treated by other physicians or prescribers and in the past 8 years I have seen exactly 1 patient with unipolar depression who was being treated with lithium augmentation.  It is far more common to see patient taking 2-4 antidepressants (typically SSRI + bupropion + trazodone or mirtazapine) or an antidepressant plus lamotrigine as the augmentation strategy.  A similar study with a cohort of American patients would be very useful to look at questions about the efficacy of lithium versus the antidepressant polypharmacy or lamotrigine - but my concern would be that there would not be a large enough sample of patients taking lithium.

It may be up to clinicians who are used to lithium therapy and the application to unipolar depression to reintroduce the practice and collect data on what the outcomes are relative to standard antidepressant augmentation strategies. Overall this study from a group of pharmacoepidemiologists provides compelling data to take a second look at an old strategy instead of just adding more antidepressants.  The data looks so good, lithium is so inexpensive, and in the USA we are in an absolute vacuum of lithium non-use for unipolar depression.   Inpatient treatment for depression has become so atrocious that it has never been more important to help people stay out of the hospital. That is why I considered this to be an important paper. 


George Dawson, MD, DFAPA

       

References:

1:   Goodwin, FK, Jamison, KR. Manic-depressive illness. New York: Oxford University Press, 1990: pp.693-696.

2: Tiihonen J, Tanskanen A, Hoti F, Vattulainen P, Taipale H, Mehtälä J,Lähteenvuo M. Pharmacological treatments and risk of readmission to hospital for unipolar depression in Finland: a nationwide cohort study. Lancet Psychiatry. 2017 Jul;4(7):547-553. doi: 10.1016/S2215-0366(17)30134-7. Epub 2017 Jun 1. PubMed PMID: 28578901.

3: Prien RF, Klett CJ, Caffey EM Jr. Lithium carbonate and imipramine inprevention of affective episodes. A comparison in recurrent affective illness. Arch Gen Psychiatry. 1973 Sep;29(3):420-5. PubMed PMID: 4579507.

4: Prien RF, Caffey EM Jr, Klett CJ. Prophylactic efficacy of lithium carbonate in manic-depressive illness. Report of the Veterans Administration and National Institute of Mental Health collaborative study group. Arch Gen Psychiatry. 1973 Mar;28(3):337-41. PubMed PMID: 4569674.

5: Coppen A, Noguera R, Bailey J, Burns BH, Swani MS, Hare EH, Gardner R, MaggsR. Prophylactic lithium in affective disorders. Controlled trial. Lancet. 1971 Aug 7;2(7719):275-9. PubMed PMID: 4104974.

6: Baastrup PC, Poulsen JC, Schou M, Thomsen K, Amdisen A. Prophylactic lithium: double blind discontinuation in manic-depressive and recurrent-depressive disorders. Lancet. 1970 Aug 15;2(7668):326-30. PubMed PMID: 4194439.

7: Bauer M, Bschor T, Kunz D, Berghöfer A, Ströhle A, Müller-Oerlinghausen B.Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression. Am J Psychiatry. 2000 Sep;157(9):1429-35. PubMed PMID: 10964859.


Supplementary:

Figure 1 above is directly from reference 2 with permission from Elsevier.  Licensing agreement #4270040486127.

If Your Patient Really Needs Lithium.......

I had the good fortune to work in an intense medical setting for about 22 years where I was responsible for the medical care of my patients.  In that setting I had access to excellent specialists, in fact some of the finest physicians I have seen anywhere.  They were typically involved when I had identified a medical problem that potentially complicated the psychiatric care of my patients.  In those cases - no matter what the problem was it usually came down to the question: "If your patient really needs this medication we need to continue it."  One of the most significant complications was renal failure of varying degrees while taking lithium.  Some patients on my unit were hospitalized because they had been stable on lithium but were developing renal failure and needed to be tried on another agent.  In some cases they experienced severe associated complications including delirium either from the bipolar disorder or medications used in the transition.  In some cases, they needed dialysis and renal medicine consultants would advise me on the lithium dose to try while they were receiving hemodialysis.  All of this experience led me to have a very low threshold for recognizing and acting on potential adverse effects of lithium as early as possible. 

At various points in my career, there was a question of renal failure occurred in cohorts on lithium or it was due to a different cause.  As an example, the Lithium Encyclopedia from 1983 (1) stated concisely: "There have been a growing number of reports of morphological and functional kidney damage associated with lithium use.  The actual incidence of lithium nephrotoxicity is not known.  Most researchers believe that irreversible damage is not widespread but that risk increases with length of treatment and serum lithium level."

At the time there were opinions that up to 20% of patients on long term lithium maintenance had morphological changes and functional changes primarily with water absorption but no reduced glomerular filtration rate (GFR) or renal insufficiency.  My favorite renal and electrolyte disorders text cited lithium as a compound that caused vasopressin resistant nephrogenic diabetes insipidus (NDI) (2).  More recent evidence suggests that 15-20% of patients on lithium develop a progressive decrease in GFR typically does not progress to end stage renal disease (ESRD) and dialysis but in some cases it clearly does.  These generalizations are usually based on low numbers of patients who have been identified as having a specific creatinine or GFR.  A creatinine of 2.5 mg/dl predicted progression to ESRD in most patients.  A larger study in Sweden of 3369 patients, suggested a lower threshold. In that study,  13 patients had been off lithium for 2 years before starting dialysis and 11 had a creatinine of > 1.4.  Some were lower but there had been a progressive increase from baseline suggesting the rate of change is important.  Additional factors such as the use of NSAIDS and ACE inhibitors like lisinopril as well as other intrinsic kidney diseases can be a factor.

There have been a recent increase in studies that look at the side effects of lithium and in one case (6) compare lithium side effects to other typical mood stabilizers (valproate, olanzapine, questiapine).  One of the studies uses descriptive statistics and the other two involve calculations of hazard ratios for specific risks.  The results are fairly uniform in their conclusions and have been known in most psychiatry training programs for the past 10-20 years.  The articles here use the Kidney Disease Outcomes Quality Initiative (KDOQI) staging of chronic kidney disease published in 2002.   The range is from stage 1 (eGFR ≥ 90 ml/min/1.73 m² ) to stage 5 (eGFR < 15 ml/min/1.73 m² or dialysis).  For the purpose of these papers Stage 2 is an eGFR of 60-89 and Stage 3 is 30-59. As previously noted progression can occur in some cases even years after the lithium has been stopped.

The most interesting of the three papers is probably from Hayes, et al because of their strategy to look at lithium toxicity but in the context of other commonly used mood stabilizers (valproate, olanzapine, quetiapine) and the associated toxicities of these other mood stabilizers.  As a result they have a table entitled Table 2. Adverse effects during maintenance treatment that looks at these mood stabilizers and CKD (stage 3 and 4), hypothyroidism, hyperthyroidism, hypercalcemia, Type 2 diabetes mellitus, cardiovascular disease, hypertension, hepatotoxicity, and weight gain (greater than 7% and greater than 15%).  Hazard ratios care calculated for all of these adverse effects using lithium as the reference.  The number of events in each category is relatively low compared with the total events in a large clinical sample.  The adverse events described were expected.  They estimated the rate of severe CKD (stage 4 or 5) as 1 in 100 person years at risk.  The estimated rates of stage 3 and stage 4 CKD were 9 in 100 per years at risk.  Hepatotoxicity was rare in the sample and was elevated in the quetiapine group.  Weight gain was most significant for olanzapine, quetiapine, and valproate relative to lithium.  Olanzapine also had the highest rate of new onset hypertension.

None of this information deters me from offering lithium to people who I think are good candidates.  The rationale is that lithium can be a life changing medication, especially for people who have generally never achieved mood stabilization with all of the typical medications prescribed for mood disorders these days.  Informed consent should include this potential complication.  I generally advise people that there is a 40% risk of NDI of varying severity, the need for ongoing testing, the need to avoid additional medications that may complicate the use of lithium, and finally close self monitoring of both side effects and any situation that can complicate lithium therapy like conditions leading to dehydration.  I will add the risk of mild CKD and explain to the patient what that means.

One of the interesting aspects of these articles is that ongoing screening for patients on lithium therapy varies considerably from setting to setting.  National guidelines seem to help.  In these large scale studies there is not enough discussion of work at the clinical level incorporating the red flags from the research.  For example it is obviously important to know about new medications, especially ACEIs, NSAIDs, and serotonergic medications.  Medications that may complicate interpretation of lab finding like Vitamin D and Calcium supplementation in the case of hypercalcemia are also important.  The review of systems is also important anywhere along the spectrum of side effects including neurological, cognitive, gastrointestinal, and renal symptoms.  I generally advise patients that increasing nocturia, polyuria, and polydipsia with associated laboratory finding increases the risk of irreversible renal changes including a low risk of progression to ESRD.  The presence of edema may indicate the rare onset of a nephrotic syndrome that can occur is some people with acute treatment.

The good news is that even now there is an accumulating literature on the potential complications of lithium therapy and some general ideas about what psychiatrists should do about it.  Although the methodology of these studies varies significantly they generally come to similar conclusions about the effect of lithium on renal function, thyroid function, and calcium metabolism.  All of these systems require close monitoring by assessing the patients clinical status and lab testing.  Numerous changes in clinical status should result in departures from any monitoring routine.  The critical elements is communication with the patient and education about when the psychiatrist should be contacted.
   

George Dawson, MD, DFAPA 


References:

1:  Jefferson JW, Greist JH, Ackerman DL.  Lithium Encyclopedia for Clinical Practice.  American Psychiatric Press, Inc. 1983: p151.  

2:  Schrier RW (ed).  Renal and Electrolyte Disorders, 2nd Ed.  Little, Brown and Company, Inc.  Boston 1980: p. 31.

3:  Lerma VE.  Renal toxicity of lithium. In UpToDate.  Sterns RH, Sheridan AM (eds) (Accessed on January 2, 2018).

4: Bendz H, Schön S, Attman PO, Aurell M. Renal failure occurs in chronic lithiumtreatment but is uncommon. Kidney Int. 2010 Feb;77(3):219-24. doi: 10.1038/ki.2009.433. Epub 2009 Nov 25. PubMed PMID: 19940841. (see open access text).

5:  Dineen R,  Bogdanet D,  Thompson D, Thompson CJ,  Behan LA,  McKay AP, Boran G,  Wall C, Gibney J, O’Keane VO, Sherlock M.   Endocrinopathies and renal outcomes in lithium therapy: impact of lithium toxicity.  QJM: An International Journal of Medicine, Volume 110, Issue 12, 1 December 2017, Pages 821–827, https://doi.org/10.1093/qjmed/hcx171

6: Hayes JF, Marston L, Walters K, Geddes JR, King M, Osborn DP. Adverse Renal, Endocrine, Hepatic, and Metabolic Events during Maintenance Mood Stabilizer Treatment for Bipolar Disorder: A Population-Based Cohort Study. PLoS Med. 2016 Aug 2;13(8):e1002058. doi: 10.1371/journal.pmed.1002058. eCollection 2016 Aug. PubMed PMID: 27483368.

7: Shine B, McKnight RF, Leaver L, Geddes JR. Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data. Lancet. 2015 Aug 1;386(9992):461-8. doi: 10.1016/S0140-6736(14)61842-0. Epub 2015 May 20. PubMed PMID: 26003379.
    

The Nocebo Effect In Antidepressant Trials

Early in my career I was an assistant to principle investigators who were doing clinical trials of drugs to treat generalized anxiety disorder, major depression, schizophrenia, and Alzheimer's Disease.  My job was top screen patients, do medical histories and physical examination, and follow them throughout the research protocol.  That is not an easy job.  The difficult part is making sure that the research patients are not getting any medical complications from a new and experimental drug in addition to assessing any possible therapeutic effects.

One of the main complications was the nocebo effect.  With all of the hype about placebo effects with antidepressants, I have always found it curious that few mention the nocebo and how it affects clinical research.  In those early days it was possible to break the blind and if research subjects withdrew from the protocol to let them know if they were taking active drug or placebo.   An adverse reaction to placebo is the nocebo effect.  It was common in these protocols for research subjects to either stop the protocol due to adverse effects or describe severe side effects while they were taking placebo.

One of the main problems I encountered with this effect in clinical trials that is an even bigger problem today is loss of research subjects who terminated early due to nocebo effects.  In the example I gave the patients developed significant side effects in response to a placebo, but people can also develop dramatic side effects to the active research medication.  Whether they are more likely to get the effect from active drug or an active placebo over the active study drug has not been actively studied.  These are critical questions because FDA trials now require and Intent To Treat Analysis for clinical trials.  That means all of the research subjects who did not complete the protocol for whatever reason need to be included in the analysis.  That becomes a problem when any subject has not been treated with the active drug - both in terms of true response but also side effects reporting.  All FDA package inserts contain detailed information on medication side effects.  Today in many cases there is a side effect comparison between active drug and placebo. Nocebo related data can skew the side effect data reported in the package inserts.    

I always thought that antidepressant trials were the ideal setting to study nocebo effects and came across a paper two years ago that does that (1).  That time frame over the last two years was an interesting one.  We saw all of the speculations about the release of the DSM-5 in the summer of 2015.  Much of that speculation involved sensational articles in the media suggesting that antidepressant medications did not work or ate least were no better than the placebo effect. Further speculation suggested that pharmaceutical manufacturers and the American Psychiatric Association (via the DSM-5) had an interest in broadening the market for antidepressants and increasing their use. At no point did any of the critics suggest that their may be a serious problem with clinical trials based on the nocebo effect.  And most interestingly, many of the critics in non-professional forum complained mostly about the side effects of these medications.  In some cases they described these medications as very dangerous.

The paper in reference 1 looks only at people receiving placebo in a pooled sample of placebo-arm data from 20 industry-sponsored multi-site randomized clinical trials of antidepressant medication in the treatment of acute major depression.  Adverse event data was recorded for all 20 clinical trials.  Adverse events (AE) can be pre-existing nonspecific somatic symptoms.  Treatment emergent adverse events (TEAE) were events that occurred or worsened during placebo treatment.  The adverse events were obtained by open ended questioning and in clinical trials from that period (1993-2010) were listed on standard forms.  Five endpoints were studied including any AE, any treatment related AE, any severe AE, any serious AE resulting in discontinuation from the study, and discontinuation form the study for any reason.  Worsening of clinical symptoms was also measured and defined as any increase in the depression rating score on any scale used for that particular study.

The main results included:

1.  TEAEs from placebo were reported in 1,569/2,457 or 63.9% of the study participants.

2.  11.2% (274) of the participants had worsening depression rating scores during the placebo treatment.

3.  4.7% (115) of the participants discontinued the study due to an AE during the placebo treatment.     

Just considering those results and nothing more illustrates the nocebo problem with current state-of-the-art clinical trials technology.  If 63.9% of the placebo-treated subjects experience side effects - what does that translate to in terms of subjects taking the active drug getting side effects unrelated to that drug?  Although untreated depression might be expected to worsen - how much of that is nocebo modulated and how much crosses over to the active drug.  A significant number of people dropped out of the trial due to the nocebo effect.  The main results suggest that in randomized placebo controlled trials of efficacy and safety - the nocebo effect is substantial.  Since the observed TEAEs and percentage of research subjects worsening on placebo was substantial - extension to TEAEs, worsening, and dropping out in clinical practice could be expected.  That would be a very difficult problem to research due to a lack of standardization across practices.

The authors did not stop with those results.  They looked at additional variable to see if there was any evidence to confirm either of the two major hypotheses about the nocebo effect.  The first is a conditioning hypothesis.  In this effect, prior exposure results in the expectation of an associated effect.  They cite as an example, women receiving chemotherapy for breast cancer and how an associated stimulus led to more nausea in the conditioned group (4).  In this case they looked at previous treatment with antidepressants as a possible conditioning effect and did not find any significant associations.

The other major hypothesis regard the nocebo effect is an expectation hypothesis.  They cite an example where a sample of college students were given inert placebo and told that it was an herbal supplement for cognitive enhancement (5).  They were provided with a fictitious list of potential benefits and side effects.  Symptoms were endorsed by most students but the students who believed that they received the active supplement endorsed more symptoms suggesting that their expectation of supplement and effect affected their perception.  They found some support that previous treatment with Hypericum perforatum (St. John's Wort) may have been associated with a greater likelihood of reporting TEAEs and suggest that users of complementary medications may be more suspect of medical pharmacotherapy.

The paper is a fairly concise review of demographic and neurobiological factors associated with the nocebo effect.  On the neurobiological side they cite the work of Enck, et al (6).  Elman and Borsook (7) have an interesting paper that looks at addiction, pain, and several common substrates of the placebo and nocebo effects.             

The take home message for me is what I have known for over a decade at this point. Current clinical trials technology in psychiatry and medicine is general is very primitive.  The evidence-based movement has had its day if this is the kind of evidence they are considering.  Why would anyone expect much more than a mild to moderate effect from a medication used for heterogeneous disorders when the true effect of the medication is significantly affected by two factors that are never measured?  This suggests areas for improvements in clinical trials that could render much of what has been collected so far - obsolete.

A final observation comes to mind and that is a phenomenon that I wrote about on this blog many years ago.  People with little to no expertise in psychiatry or medicine don't hesitate to criticize the field.  A good example would be people who have never treated a single case of depression much less thousands of cases who do a meta-analysis and claim that antidepressants are placebos.  I don't recall any of these critics in the popular press considering the limitations of clinical trials.  Without that basic consideration any theory that fits the apparent data can apply.

What would be useful at this point would be detailed analyses of the placebo arm of all clinical trials and a discussion of how these effects might bias the data.  Actual interventions to quantify or eliminate these effects in future trials is the next step.  These are more practical steps than hoping for mythical large clinical trials with slightly more sophisticated clinical trials technology that epidemiologists and the Cochrane Collaboration routinely recommend.         


George Dawson, MD, DFAPA

References:

1: Dodd S, Schacht A, Kelin K, Dueñas H, Reed VA, Williams LJ, Quirk FH, Malhi GS, Berk M. Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials. J Clin Psychiatry. 2015 Jun;76(6):702-11. doi: 10.4088/JCP.13r08858. PubMed PMID: 26132671.

2:  Gupta SK. Intention-to-treat concept: A review. Perspectives in Clinical Research. 2011;2(3):109-112. doi:10.4103/2229-3485.83221.

3:   Interactions between brain and spinal cord mediate value effects in nocebo hyperalgesia” by A. Tinnermann, S. Geuter, C. Sprenger, J. Finsterbusch, C. Büchel in Science. Published online October 5 2017 doi:10.1126/science.aan122

4:  Bovbjerg DH, Redd WH, Jacobsen PB, Manne SL, Taylor KL, Surbone A, Crown JP,Norton L, Gilewski TA, Hudis CA, et al. An experimental analysis of classically conditioned nausea during cancer chemotherapy. Psychosom Med. 1992 Nov-Dec;54(6):623-37. PubMed PMID: 1454956.

5: Link J, Haggard R, Kelly K, Forrer D. Placebo/nocebo symptom reporting in asham herbal supplement trial. Eval Health Prof. 2006 Dec;29(4):394-406. PubMed PMID: 17102062.

6: Enck P, Benedetti F, Schedlowski M. New insights into the placebo and nocebo responses. Neuron. 2008 Jul 31;59(2):195-206. doi: 10.1016/j.neuron.2008.06.030. Review. PubMed PMID: 18667148.

7: Elman I, Borsook D. Common Brain Mechanisms of Chronic Pain and Addiction. Neuron. 2016 Jan 6;89(1):11-36. doi: 10.1016/j.neuron.2015.11.027. Review. PubMed PMID: 26748087.



Attributions:

Figure at the top is stock photo from Shutterstock per their licensing agreement by kasezo entitled:

Stock illustration ID: 284558927   conceptual 3d design of false pill.( placebo and nocebo effect.red and green colored version)